What every physician needs to know:

Endometrial carcinoma is the most common gynecological malignancy of the female reproductive tract. In 2010 it is estimated that 43,000 women will be diagnosed with endometrial cancer, while 8000 will die from the disease. The median age at diagnosis is 61 years.

Two clinico-pathological types of endometrial cancer have been described in the literature.

The remaining endometrial malignancies are mesenchymal tumors and consistent of endometrial stromal sarcomas, leiomyosarcomas, and adenosarcomas.

Carcinosarcoma of the uterus is a rare malignant uterine neoplasm that contains both carcinomatous and sarcomatous elements. These neoplasms are regarded as rare aggressive malignancies with a high potential to develop distant metastases and are associated with an overall poor survival. Although the histogenesis of this neoplasm has been debated, evidence has begun to accumulate that this neoplasm may be more closely linked to carcinoma than to sarcoma.

Are you sure your patient has endometrial cancer? What should you expect to find?

The vast majority of patients with endometrial cancer present with abnormal vaginal bleeding. At times, patients present with a watery blood-tinged discharge. Other symptoms include dyspareunia, dysuria, pelvic pain, abdominal bloating, and constipation.

Beware of other conditions that can mimic endometrial cancer

Vaginal bleeding in post-menopausal women is a cardinal symptom of uterine cancer. As such, other conditions that mimic endometrial cancer are those that present with abnormal vaginal bleeding.

It is important to note that vaginal bleeding is often attributed to a uterine source, but may arise from disease at any anatomic site in the lower genital tract (vulva, vagina, and cervix) or upper genital tract (uterine corpus, fallopian tubes, ovaries) or urethra, bladder, or bowel.

Other states that present with abnormal bleeding and can mimic endometrial cancer include:

Other disorders that can often masquerade as an endometrial malignancy include:

cervicitis

cervical polyps

endometriosis

vasculitis

vaginitis

vaginal and/or vulvar malignancies

vaginal trauma

fistulas (such as vescicovaginal or rectovaginal fistulas)

disease of the urethra

systemic diseases (such as Crohn’s disease).

Which individuals are most at risk for developing endometrial cancer:

Uterine cancer is the most common gynecologic malignancy in the United States with a median age of diagnosis of 61. Women have a 2.5% lifetime risk of developing endometrial cancer, which accounts for 6% of all cancers in women.

Fortunately, most cases are diagnosed at an early stage when surgery alone may be adequate for cure. Incidence rates are higher in white women rather than in black, Hispanic or Asian/Pacific Islander women. However, mortality is almost two-fold higher in black population (7.1 versus 3.9 per 100,000 women) likely due in part to the higher incidence of aggressive cancer subtypes.

The risk factors associated with Type I adenocarcinoma of the uterus include states related to excess estrogen stimulation. Excess estrogen stimulation can be derived from either an endogenous and exogenous source. Endogenous sources of estrogen excess include obesity, while exogenous sources relate to unopposed estrogen replacement therapy or tamoxifen.

Women with diabetes mellitus and hypertension are at increased risk for endometrial cancer. Advancing age is also a risk factor. Endometrial cancer usually occurs in post-menopausal women. However, it is important to note that 25% of cases are diagnosed in pre-menopausal women.

Lynch syndrome (hereditary nonpolyposis colorectal cancer) is also a risk factor for endometrial cancer. The lifetime risk of endometrial cancer is 27-71% compared with 3% in the general population. The mean age at endometrial cancer diagnosis in women with Lynch syndrome is 46-54 years, compared with a mean age of 60 years in other women.

Although there are no commonly described risk factors for type II endometrial cancers, there is some speculation that patients with BRCA1/2 mutations may be at risk for uterine papillary serous cancer.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

Endometrial biopsy (EMB)

EMB helps establish a tissue diagnosis of endometrial cancer.

Surgical staging

Surgical staging is critical for determining prognosis and in navigating treatment in endometrial cancer. A standard surgical approach includes a total abdominal hysterectomy, bilateral salpingo-opherectomy with or without lymph node dissection, and peritoneal washings.

The staging algorithm has launched several debates regarding the importance in determining lymph node status. In the UK, Medical Research Council ASTEC trial, 1408 patients were randomized to standard practice with and without lymph node dissection. There was no difference in 5-year disease-free survival and overall survival. However, in patients who underwent lymph node resection there was a higher incidence of complications such as the development of an ileus, thrombotic events and wound healing. As such, the relevance of determining lymph node status in all patients remains a controversial topic.

Minimal risk procedures are currently being investigated in the surgical management of patients with endometrial cancer. Laparoscopy has been evaluated as an alternative to the traditional procedure. Preliminary studies have reported fewer complications and shorter hospital stays with laparoscopic procedures. Robotic-assisted surgery is also a minimally invasive surgery for endometrial cancer and is gaining popularity in many tertiary care centers.

Regardless of method, surgical staging of endometrial cancer defines the stage, grade, depth of invasive disease and the histological subtype. Endometrial carcinoma is staged according to the International Federation of Gynecology and Obstetrics (FIGO) system.

Basic laboratory tests

Complete blood count with differential and chemistry profile including serum creatinine, electrolytes and liver function tests should be obtained. Anemia is not uncommon in patients with endometrial cancer. A Ca125 is not commonly utilized in type I uterine cancers. In papillary serous carcinoma of the uterus this marker may have utility.

Imaging studies

Computerized tomography (CT), magnetic resonance imaging (MRI) and Positron–emitting tomography (PET) have been evaluated in the staging of endometrial carcinoma. Imaging studies help to differentiate between organ-confined or locally advanced disease.

Cross-sectional imaging studies may underestimate the true extent of pelvic regional lymph node metastases; however, visceral (e.g. liver, adrenal glands) or skeletal metastases may be identified. A study examining the role of PET/CT in staging patients with endometrial cancer was reported to have a specificity of 95% in detecting disease outside of the uterus.

It is important to note that no imaging studies are a substitute for surgical staging.

Staging

Table I. TNM and FIGO staging of endometrial carcinoma.

Table I.

TNM Staging of Uterine Carcinoma

Table II. TNM and FIGO staging of endometrial sarcoma.

Table II.

TNM Staging of Leiomyosarcoma and Endometrial Stromal Sarcoma

What therapies should you initiate immediately i.e., emergently?

Management of patients with vaginal bleeding

A thorough history and physical examination should be obtained. Presence of hereditary or acquired coagulopathies should be recognized. A careful review of current medications is key. Use of anticoagulant, antiplatelet, and non steroidal anti-inflammatory medications should be recognized.

Blood type and cross-match should be obtained for patients who require urgent or emergent transfusion of leukocyte depleted packed red blood cells. A gynecological surgical consultation is of paramount importance.

Several therapeutic options exist for uterine bleeding not attributable to malignancy. These include:

1. Intrauterine tamponade - Intrauterine tamponade can be achieved using either an intrauterine balloon or gauze packing.

2. Uterine curettage — Uterine curettage is the treatment of choice for profuse uterine bleeding in women who are hemodynamically unstable.

3. High dose intravenous estrogen (IV) — High dose IV estrogen is beneficial in combination with other measures in hemodynamically unstable women with acute uterine bleeding. Of note, pulmonary embolism and thrombosis at other sites are potential complications of high dose estrogen therapy. Care must be individualized.

4. Uterine artery embolization — Uterine artery embolization as a first-line therapy is reserved for women in whom the etiology of bleeding is a uterine arteriovenous malformation, since it is the most effective treatment for this condition.

6. High dose oral contraceptives — High doses of oral contraceptives (OCs) (e.g. an OC containing 35mcg ethinyl estradiol taken two to four times daily) will cause bleeding to subside in most women within 48 hours.

7. High dose progestins — Profuse or prolonged uterine hemorrhage related to anovulation can also be treated with high dose progestins alone.

8. Tranexamic acid — Another medical therapy option is tranexamic acid (1 to 1.5g orally, three to four times daily), which acts within two to three hours of administration.

9. Endometrial ablation is an effective treatment for acute or prolonged uterine bleeding and is used in stable women in whom medical therapy is contraindicated or unsuccessful.

Options must be individualized as hormonal therapy can have significant consequences.

What should the initial definitive therapy for the cancer be?

Surgery, radiation therapy, hormone therapy and chemotherapy are used either alone or sequentially to treat endometrial carcinoma depending on disease stage and histological grade. Currently, patients are most commonly staged by the 2009 FIGO staging system (see Table I).

Initial management of uterine cancer

Surgery

The surgical approach to endometrial cancer is described in "Surgical Staging" above. In contrast to many other solid tumors, for endometrial cancer surgery often has a role even in locally advanced or distant disease.

Radiation Therapy

Radiation therapy consists of external beam radiation therapy (EBRT) and intravaginal irradiation. The dose of radiation for adjuvant therapy is 45 to 60 Gy. The total dose is typically fractionated or spread out over time. Standard EBRT is delivered in once daily fractions, typically 1.8 to 2 Gy, five days a week, for a period of weeks. Fractionation decreases the amount of toxicity to healthy tissues by exploiting their innate capacity for sublethal damage repair and repopulation compared to malignant tissues.

Brachytherapy represents an important part in the treatment of endometrial carcinoma but must be individualized. Brachytherapy can be delivered with either a low dose rate (LDR) or high dose rate (HDR) system. For vaginal brachytherapy, the dose should be prescribed to the vaginal surface or at a depth of 0.5cm from the vaginal surface; the dose depends on the use of EBRT.

For HDR brachytherapy, when used as a boost to EBRT, doses of 4-6 Gy X 2-3 fractions prescribed to the vaginal mucosa are commonly used. For HDR vaginal brachytherapy alone, extended field, the target for vaginal brachytherapy after hysterectomy should be limited to the upper vagina. Commonly used regimens include 7 Gy X 3 prescribed at a depth of 0.5cm from the vaginal surface or 6 Gy X 5 fractions prescribed to the vaginal surface.

The role of adjuvant radiation in early stage endometrial cancer has been evaluated in several major trials. Table IV highlights the various trials that reference the loco regional benefit derived from radiation therapy.

Table IV.

Clinical trials of chemotherapy for advanced uterine cancer

Data derived from four randomized trials (NORWEGIAN, PORTEC-1, GOG-99 and ASTEC/EN.5) evaluated the role of adjuvant pelvic EBRT in patients with early-stage endometrial cancer. Despite the differences in eligibility criteria, these studies established the significant benefit of adjuvant EBRT in preventing isolated locoregional recurrence, but failed to demonstrate any improvement in overall or disease-specific survival.

Recently published were the results of the PORTEC-2 trial, that randomly assigned 427 patients with stage I or IIA endometrial carcinoma of high-intermediate risk features (age = 60 years and stage IC grade 1 or 2 disease or IB grade 3 disease; any age and stage IIA with grade 1 or 2 disease or grade 3 and <50% myometrial invasion) to adjuvant vaginal brachytherapy or pelvic EBRT.

Both treatment modalities were found equivalently effective in preventing vaginal (5-year rate 1.8% vs. 1.6%, P=0.74), locoregional (5-year rate 5.1% vs. 2.1%, P=0.17) and distal (5-year rate 8.3% vs. 5.7%, P=0.46) recurrence with no substantial differences in overall survival (84.8% vs. 79.6%, P=0.57). Vaginal brachytherapy was recommended as treatment of choice for high-intermediate risk patients with early stage disease as of providing an excellent local control with less morbidity.

Chemotherapy

Based on data from several important clinical trials listed in Table III, there is now frequent use of chemotherapy in conjunction with radiation therapy for first-line treatment of women with advanced disease (Stage III) after initial surgery. In patients that have distant or visceral disease chemotherapy alone is often used.

Table III.

Clinical trials of radiation therapy for uterine cancer

Upfront radiation therapy with cisplatin (50mg/m2; on days 1 and 28) as a radiosensitizer followed in sequence with 4 cycles of a platinum and a taxane (RTOG 9708).

A "sandwich approach": namely three cycles of carboplatin (AUC 5-6) and paclitaxel (175mg/m2;) every three weeks followed in sequence with radiation therapy (external beam radiation therapy/vaginal brachytherapy) followed in sequence with three additional cycles of carboplatin and paclitaxel. Caution must be entertained post radiation therapy as patients may encounter profound myelosuppression. At times paclitaxel is dosed reduced to 135mg/m2;. The use of neulasta or neupogen is encouraged in the appropriate population, i.e. elderly.

For historical purposes, Table IV and Table V highlight the available studies to date. The most commonly and best tolerated regimen is carboplatin (AUC 5-6) with paclitaxel (175 mg/m2;). Doses may need modification if chemotherapy is given post-radiation therapy.

Management of recurrent disease

The use of hormonal agents is a therapeutic option in the management of patients with relapsed endometrial cancer. Progestin therapy has been studied in several GOG trials. The overall response rated to progestin therapy ranges from 18-34% with a progression free survival of 3 months.

Endocrine Therapy

In one GOG trial (GOG 153) the investigators utilized an alternating schedule of Megace (80mg BID) and tamoxifen (20mg BID) in a 3 week interval. The overall response rate was 27%. The median progression free survival was 2.7 months and the median overall survival was 14 months. Other agents commonly employed included aromatase inhibitors and GnRH agonists. However, the latter agents are reported to have only marginal activity. Commonly Megace 80-160mg every day is utilized as endocrine therapy.

Chemotherapy

Depending on the initial treatment of disease at presentation, options can include:

Carboplatin AUC5-6 and paclitaxel (175mg/m2;) every three weeks for six cycles.

An anthracycline based regimen (i.e. doxorubicin 60mg/m2; every 3 weeks).

Topotecan (dose: 3-4mg/m2; on days 1,8,15 every 28 days).

Docetaxel 36mg/m2; weekly.

Ixabepilone 50mg/m2; every 3 weeks.

It is important to note that the doses outlined above represent the doses originally studied and may not be suitable for all patients given their prior exposures to various therapy. Given the limited options available in the recurrent setting clinical trial enrollment is of paramount importance.

Biologic agents under investigation

Numerous molecularly targeted therapeutics are currently being investigated in the management of patients with advanced endometrial cancer.

One of the most common alterations in endometroid adenocarcinoma is a mutation in a gene encoding the phosphatase and tension homologue (PTEN). PTEN is a regulator of the PI3K/AKT/MTor pathway. Numerous phase II trials with mTOR inhibitors have shown activity in the management of recurrent disease. These agents include Temsirolimus, Deforolimus and Everolimus. Current studies are focused on dual inhibitors of this pathway with agents that target PI3K, PTEN, AKT, and MTor.

In addition to agents that target the mTOR pathway, agents targeting aberrant angiogenesis have also entered clinical practice. Aghajanian and colleagues recently published data on the use of bevacizumab in patients with advanced uterine cancer. The authors reported a 6 month progression free survival of 40%. Currently numerous studies combining biological targeted agents and cytotoxic therapy are underway (GOG 86P). Current guidelines for treatment are derived form the NCCN version 1.2012.

When chemotherapy and radiation therapy is deemed appropriate (Stage III A, B, C) there are several options to consider including (1) upfront radiation therapy with cisplatin (50mg/m2; on days 1 and 28) as a radiosensitizer followed in sequence with 4 cycles of a platinum and a taxane (RTOG 9708) or (2) a "sandwich approach": namely three cycles of carboplatin (AUC 5-6) and paclitaxel (175mg/m2;) every three weeks followed in sequence with radiation therapy (external beam radiation therapy/vaginal brachytherapy) followed in sequence with three additional cycles of carboplatin and paclitaxel.

Caution must be entertained post-radiation therapy as patients may encounter profound myelosuppression post-radiation therapy. At times, paclitaxel doses are reduce to 135mg/m2;. The use of neulasta or neupogen is encouraged in the appropriate population, i.e. elderly.

Stage IIIB and Stage IIIC (Chemotherapy and/or tumor-directed RT)

When chemotherapy and radiation therapy is deemed appropriate (Stage III A, B, C) options include upfront radiation therapy with cisplatin (50mg/m2 on days 1 and 28) as a radiosensitizer followed in sequence with 4 cycles of a platinum and a taxane (RTOG 9708) or a "sandwich approach": namely three cycles of carboplatin (AUC 5-6) and paclitaxel (175mg/m2;) every three weeks followed in sequence with radiation therapy (external beam radiation therapy/vaginal brachytherapy) followed in sequence with three additional cycles of carboplatin and paclitaxel.

Caution must be entertained post-radiation therapy as patients may encounter profound myelosuppression post-radiation therapy. At times, paclitaxel doses are reduced to 135mg/m2;. The use of myeloid growth factors is encouraged in the appropriate population, i.e. elderly.

Stage IV

Chemotherapy (outlined above)

Hormonal Therapy (outlined above)

Palliative radiation therapy (outlined above)

What other therapies are helpful for reducing complications?

Growth factor support therapy: neutropenia

Primary prophylaxis of neutropenic fever with growth factor support therapy (e.g. filgrastim or pegfilgrastim) is not routinely prescribed in patients with endometrial cancer receiving chemotherapy.

Patients who develop neutropenic fever after chemotherapy should receive growth factor support therapy with subsequent cycles of chemotherapy:

Filgrastim 5mcg/kg SC daily starting 24 hours after infusion of chemotherapy and until the absolute neutrophil count (ANC) is greater than 1000 for two to three consecutive days.

Pegfilgrastim 6mg SC 24 hours after infusion of chemotherapy. Do not prescribe pegfilgrastim within 14 days before the next chemotherapy infusion.

Growth factor support therapy: anemia

Erythropoietin stimulating agents (e.g. erythropoietin, darbepoietin) should not be prescribed in patients receiving potentially curative therapy, as some studies suggest decreased cancer-specific survival. In this setting, transfusion of leukoreduced packed red blood cells may be needed in patients who develop symptomatic or severe anemia.

Management of bone metastases

Short course palliative external beam radiotherapy may be considered for painful bone metastatic lesions.

The parenteral bisphosphonate zoledronic acid or the monoclonal antibody denosumab may be utilized indicated for patients with endometrial cancer with metastases to bones. Denosumab targets the receptor activator of nuclear factor kappa-B ligand (RANKL).

Zoledronic acid 4mg IV every four weeks

Denosumab 120mg SC every four weeks

Dose reductions of zoledronic acid are needed in patients with renal dysfunction. In patients with advanced renal insufficiency (GFR < 30mL/min), zoledronic acid should not be prescribed. Patients receiving zoledronic acid or denosumab should take oral calcium and vitamin D supplementation.

Osteonecrosis of the jaw is a potential complication of treatment with zoledronic acid or denosumab. A careful exam of the oral cavity should be done in patients receiving these agents.

What should you tell the patient and the family about prognosis?

The most important prognostic factors at diagnosis are stage, grade, depth of invasive disease and histological subtype. The five-year survival rate for women diagnosed with endometrial cancer is stage dependent:

Stage I - 86 %

Stage II - 66%

Stage III - 44%

Stage IV - 16%

Of note, Caucasian women have a higher survival rate than non-white patients at each disease stage.

What if scenarios.

Early stage high-risk uterine cancer

A high-risk population of early stage endometrial cancer patients exists. Certain subgroups of patients with Stage I-II endometrial cancer have been shown to have a higher risk of recurrence.

These patients may derive benefit from some form of post-operative adjuvant therapy. In the clinical trial GOG-99 a subgroup of patients with “high-intermediate risk” (H-IR) were identified. Risk criteria included Grade 2-3 tumors, presence of lymphovascular space involvement (LVSI), and outer 1/3 myometrial invasion.

Patients were classified as H-IR if they were at least 70 years with any one factor, at least 50 years with any 2 factors, or any age with all 3 factors. The cumulative risk of recurrence without therapy at 48 months was 27% for this group.

An appropriate management course for these individuals is enrollment in the clinical trial GOG 249, a phase III trial of pelvic radiation therapy versus vaginal cuff brachytherapy followed by paclitaxel/carboplatin chemotherapy in patients with high risk, early stage endometrial carcinoma.

Carcinosarcoma of the uterus

There has been no established consensus regarding adjunctive therapy for patients with uterine carcinosarcoma (CS). Five-year survival figures for patients with carcinosarcoma are poor and have ranged from 0-35%.

The frequency of visceral, intra-abdominal and extra-abdominal metastases even in patients initially staged as Stage I or II disease emphasize the virulence of this tumor and demonstrate the need for effective systemic therapy.

The estimated death rate was 29% lower among the CIM group (RH=0.712, 95% CI: 0.484-1.048, p=0.085, two-tail test). Current management of patients with carcinosarcoma of the uterus commonly employs dual modality therapy with systemic chemotherapy - carboplatin and paclitaxel followed by radiation therapy.

Stage IA uterine papillary serous carcinoma

Uterine papillary serous carcinoma (UPSC) is a histological variant of endometrial cancer that accounts for only 10% of new cases of uterine cancer but is responsible for 40% of deaths from the disease.

UPSC is an aggressive tumor with a predilection for early spread beyond the uterus. Schwartz et al retrospectively reviewed 74 stage I patients with UPSC who underwent complete surgical staging. Stage IA patients were divided into two groups: patients with no cancer in the hysterectomy specimen (defined as no residual uterine disease) and patients with cancer in the hysterectomy specimen (defined as residual uterine disease).

However, 6 of 14 (43%) stage IA patients with residual uterine disease who did not receive chemotherapy recurred. The authors concluded that platinum-based chemotherapy was associated with improved disease-free survival (P < 0.01) and improved overall survival (P < 0.05) in patients with stage I UPSC. As such stage IA patients are often treated with six cycles of carboplatin and paclitaxel followed by vaginal brachytherapy.

Follow-up surveillance and therapy/management of recurrences.

The recommended post treatment surveillance includes:

physical exams every 3-6 months for 2 years

vaginal cytology every 6 months for 2 years

patient education regarding worrisome symptoms

CT/MRI scans if symptoms surface

genetic counseling for patients with a significant family history or patients diagnosed at a young age.

Pathophysiology

Data on the molecular pathogenesis of endometrial carcinoma is starting to emerge. It is important to note that the pathogenesis of uterine cancer is specific to histological variant of uterine cancer. In Type I carcinomas of the uterus numerous genetic abnormalities have been identified in both endometrial hyperplasia and endometroid carcinoma.

Microsatellite instability has been documented in endometrial cancers. Mutations in the mismatch repair genes, most commonly in MLH1 and MSH2, were initially reported in hereditary nonpolyposis colorectal cancer (HNPCC). Microsatellite instability has been associated with 75% of HNPCC-related endometrial cancers and 20-30% of sporadic endometrial tumors. It has also been reported in complex and atypical endometrial hyperplasia, suggesting a role in the initial stages of endometrial tumorigenesis.

Point mutations have been identified in the K-ras gene in endometrial cancers. Mutations in the K-ras proto-oncogene are not present in normal endometrium and are therefore thought to contribute to the tumorigenesis of endometrial cancers. Mutations in codons 12 and 13 have been described in almost 40% of endometrial cancers and 6 to 16 percent of atypical endometrial hyperplasia.

PTEN/AKT pathway and its downstream targets and the mTOR (mammalian target of rapamycin) pathway have been shown to play an important role in endometrial cancer pathogenesis. Inactivation of PTEN usually occurs as a result of either a deletion or a mutation.

Mutations in the PTEN gene have been reported in both typical and atypical endometrial hyperplasia. Loss of PTEN expression has been found in 30-60% of endometrial hyperplasia. It is believed to be involved in the initial stages in the tumorigenesis of endometrial cancers.

Other potential targets that are currently being explored as potential navigators of tumorigenesis include the FOXO 1 transcription factor as well as IGF-1 and IGF-2.

In Type II endometrial cancers there is evidence that suggests that p53 plays a central role in the tumorigenesis of endometrial cancers. Research has demonstrated an increase in the over expression of the p53 protein from normal endometrium to hyperplasia through to endometrial carcinoma, suggesting a possible role in disease progression in endometrial carcinoma. Up to 85% of type 2 cancers have been found to have p53 over expression compared with 10-20% of type 1 cancers.